Available evidence on HIFU for focal treatment of prostate cancer: a systematic review

ABSTRACT Purpose: Prostate cancer (PCa) is the second most common oncologic disease among men. Radical treatment with curative intent provides good oncological results for PCa survivors, although definitive therapy is associated with significant number of serious side-effects. In modern-era of medicine tissue-sparing techniques, such as focal HIFU, have been proposed for PCa patients in order to provide cancer control equivalent to the standard-of-care procedures while reducing morbidities and complications. The aim of this systematic review was to summarise the available evidence about focal HIFU therapy as a primary treatment for localized PCa. Material and methods: We conducted a comprehensive literature review of focal HIFU therapy in the MEDLINE database (PROSPERO: CRD42021235581). Articles published in the English language between 2010 and 2020 with more than 50 patients were included. Results: Clinically significant in-field recurrence and out-of-field progression were detected to 22% and 29% PCa patients, respectively. Higher ISUP grade group, more positive cores at biopsy and bilateral disease were identified as the main risk factors for disease recurrence. The most common strategy for recurrence management was definitive therapy. Six months after focal HIFU therapy 98% of patients were totally continent and 80% of patients retained sufficient erections for sexual intercourse. The majority of complications presented in the early postoperative period and were classified as low-grade. Conclusions: This review highlights that focal HIFU therapy appears to be a safe procedure, while short-term cancer control rate is encouraging. Though, second-line treatment or active surveillance seems to be necessary in a significant number of patients.


INTRODUCTION
Prostate cancer (PCa), with almost 1.3 million new cases and 359.000 deaths annually, is the second-most frequent oncologic disease and the fifth leading cause of cancer-related death among men (1). In the past decade, because of greater public and professional awareness as well as widespread use of molecular testing, PCa diagnosis has shifted dramatically towards earlier-stage, localized disease (2). Radical treatment with curative intent provides good oncologic results for these patients, although definitive therapy is associated with many serious side-effects (3), all of which have a significant negative impact on a man's physical and mental well-being (4). As part of the tremendous progress being made in new treatment modalities, minimally-invasive procedures, such as high-intensity focused ultrasound (HIFU), have been suggested for PCa patients with the intent of providing equivalent oncologic safety to the standard of care with a reduced side-effect profile (5). Targeting energy at a focal lesion in or on the prostate, thereby sparing surrounding, non-cancerous prostate tissue, could reduce treatment-related toxicity to the minimum level possible, thus raising interest in focal HIFU therapy is seen in uro-oncological society (6). In this systematic review, we provide the available evidence about focal HIFU therapy as a primary treatment for treatment-naïve localized PCa. Our objective is to review technical aspects of the procedure, oncologic and functional outcomes, complications, as well as retreatment options.

MATERIALS AND METHODS
This systematic review was based on recommendations by Cochrane (7) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocols (8). The review protocol was registered in the PROSPERO data-base (CRD42021235581). Web search was performed on the MEDLINE database (through Pub-Med) using the key words <prostate cancer> AND <HIFU focal therapy> OR <HIFU partial gland ablation> OR <HIFU focal therapy outcomes> OR <HIFU focal therapy complications> OR <retreatment after HIFU focal therapy>. The search was limited to articles published in the English language and reporting focal HIFU outcomes between 2010 and 2020, including meta-analyses, randomised controlled trials, prospective development studies, prospective and retrospective case series with more than 50 patients. Two authors performed abstract screening independently. In case of discrepancies, uncertainty was solved by a third author. Web search was implemented by manual search including senior authors consultation and search of included articles reference lists. Review articles, case reports, and congress abstracts as well as studies reporting whole-gland ablation or procedures performed in a salvage setting were excluded. The following data were extracted from each study: study design, study population, technical aspects of the procedure, type of anaesthesia, urinary catheter management, length of follow--up, oncologic and functional outcomes, and complications and recurrence management.
At 3 and 6 months after focal HIFU therapy, 86% to 98% (15,20,21) and 90% to 98% (19,20) of patients with PCa self-reported as totally continent, while 12 months after the procedure, complete continence was achieved in 93% to 97% of patients (10,14,15,17,20,24). No further improvement in urinary function was observed 2 to 3 years after the procedure (17). IPSS score remained unchanged during the first 6 months postoperatively (12,18,19). Interestingly, Abreu et al. (27) and Rischmann et al. (14) reported improved initial IPSS results after focal therapy, therefore, it should be highlighted that preoperative TURP in these studies was performed according to the study protocol. On the EPIC urinary domain questionnaire, the incontinence score showed initial deterioration, although 6 months after the procedure, the score had returned to baseline (19) and remained high at 2 (97% continent) and 3 years (98% continent) afterwards (13). No changes in ICSmaleSF score were detected for 85% of patients with PCa 3 months after the procedure (21), although the same improvement from baseline was observed 12 months after focal therapy (18).
According to self-reported symptoms for erectile function, 69% to 80% of patients with PCa had retained sufficient erections for sexual intercourse 6 months after focal HIFU (19,20), and these rates remained stable (14,15,17,20,24) or improved slightly (86%) (23) within the next 2 years. The total score on the 15-question IIEF questionnaire (IIEF-15) initially decreased by 23 points, with a gradual recovery during the early postoperative phase, 6 months after the procedure, the total score was still inferior by 17 points compared with baseline (19). Another study (10) evaluated erectile function in the later postoperative period (12 months) using the same IIEF-15 questionnaire, where 88% of patients reported normal erectile function. A few authors used the IIEF short-form questionnaire (IIEF-5) after focal HIFU. Abreu et al. (27) reported no deterioration in erectile function, while Feijoo et al. (12) and Ganzer et al. (18) reported that 52% to 70% of patients with PCa retained the same preoperative values on the IIEF-5 after the procedure. Just one study (17) reported ED rates after a second focal HIFU, where retreatment was associated with a 7% increased ED rate.
No negative side-effects on bowel function were detected on the EPIC bowel domain questionnaire (19), and no deterioration in QOL was registered on the FACT-P questionnaire (10,19).
Ablation volume (6) and inclusion of the urethra (16) were identified as the main predictors for postoperative complications. The majority of the patients (78%) undergoing subtotal HIFU reported having some type of complication, while more precise, lesion-targeted ablation was associated with a significantly lower (36%) risk of side-effects (6). Inclusion of the urethra in the HIFU ablation zone led to adverse events (AEs) in 48.8% of patients, while patients undergoing urethra--sparing surgery had a significantly lower (26.3%) risk of complications (16). Other risk factors included smaller prostate volume, higher body mass index, and longer bladder catheterization time (6).
Some patients with low-risk disease, mostly those harbouring ISUP grade group 1 PCa, were offered deferred treatment options. According to 5 articles (10,14,18,19,25), 4% to 35% of patients with PCa were under active surveillance after focal HIFU therapy.
Two studies (13,14) reported third-line salvage treatment after 2 focal HIFU ablation procedures, including third-line focal HIFU ablation, which was performed in 1% of patients (13), salvage RP, which was performed in 1% of patients (14), salvage EBRT, which was performed in 2% of patients (14), and ADT only, which was used in 1% of patients (14). A second focal HIFU therapy procedure was associated with increased risk (by 7%) of ED (17) but did not compromise continence (21), no serious AEs were detected after any type of salvage therapy (21,24).

DISCUSSION
Since the introduction of aggressive PSA testing into clinical practice, the diagnosis of PCa has shifted dramatically towards earlier-stage and localized disease (2). In the past decade, because of the widespread use of mpMRI and rapid progress in ultrasound and mpMRI-ultrasound fusion technologies, the more precise detection of early-stage PCa has moved towards early-stage, clinically significant disease, which carries the highest risk of progression (33). Taking into account that active treatment is crucial for this type of PCa and that whole-gland therapies are associated with serious AEs in the sexual and urinary domains (3,4), focal therapy could be a better option for these patients.
Focal HIFU focuses ultrasound waves at a malignant lesion in or on the prostate, it pro-duces heat above 65°C and destroys the targeted area through coagulative necrosis. Since the early 2000s, 3 HIFU devices have been commercially available for PCa treatment: Sonablate 500, Ablatherm, and Focal One. All three machines have been used in some of the studies included in this review: the Sonablate 500 device in 8 studies, the Ablatherm device in 8 studies, and the Focal One device in 6 studies. Some differences in technical characteristics exist between these devices, what could also have affected treatment outcomes (34). The Ablatherm and Focal One device use coupling liquid to protect the rectum; thus, patients should be placed in a lateral position to allow gas bubbles to rise outside the imaging and therapy fields. The Sonablate 500 device uses circulating chilled water instead of coupling liquid, thus, a supine patient position is recommended. The Focal One device, which features the latest technology, enables more precise pre-treatment planning and shape and size modifications during the procedure (which are not possible with the Ablatherm device) as well as end-of-treatment validation through contrast-enhanced ultrasound (which is not possible with the Sonablate 500 device) (35).
Across all the studies included in this review, tissue-preserving strategies during focal HIFU therapy were inconsistent. Based on the volume of the disease and the extension within the prostate, different treatment strategies have been proposed: index-lesion or focal ablation, quadrant ablation, hemiablation, and subtotal or hockey--stick ablation (36). After the procedure, the type and length of bladder catheterisation varied significantly among the initial studies. According to some authors (22), a suprapubic approach was based on their personal experience with whole-gland therapy and prolonged voiding problems afterwards. Thus, urethral catheterization was avoided to decrease the risk for urethral strictures. When it became clear that most men re-established voiding less than a week after the procedure, indwelling urethral catheterization for up to 3 days postoperatively was adopted as the standard approach in most of the studies. A few authors have also performed TURP in preoperative or perioperative settings to decrease postoperative sloughing and prolonged need for bladder catheterization. None of these authors has evaluated the impact of TURP on postoperative functional outcomes.
Short-term oncologic results have been reported in the majority of the studies reviewed, while just 2 studies (13,21) have reached a postoperative follow-up adequate for intermediate-term results. Taking into account the prolonged natural history of PCa and the lack of reliable comparative data on medium-and long-term oncologic outcomes, no final decision could be made regarding cancer control after focal HIFU therapy. PSA nadir in all the studies reviewed had been reached 12 months postoperatively, with a median reduction greater than 50% from baseline. Despite one author (20) using PSA kinetics to trigger postoperative biopsies, it should be highlighted that currently no accepted definition of biochemical disease control following focal therapy has been established, thus, postoperative follow-up could not be based on Phoenix (37), Stuttgart (38), or any other criteria, and postoperative mpMRI with control biopsies are mandatory (39). During short--term follow-up, half of the patients were histologically confirmed as having clinically significant (ISUP grade group ≥2) disease, where in-field and out-of-field PCa was detected in up to 22% and 29% of patients, respectively.
Retreatment possibilities have been reported in some of the studies. Therefore, no data regarding indications for different retreatment strategies, including second focal HIFU or other focal therapies, or for whole-gland treatment options were reported in any of the studies. For low--risk recurrence, a deferred treatment option was offered in the majority of the studies, where up to 35% of patients with PCa after focal HIFU were undergoing active surveillance. The majority of the studies used radical treatment options, such as salvage RP and salvage EBRT, to treat PCa recurrence or progression. Second focal HIFU was initiated in up to 20% of patients with PCa, where in-field recurrence was treated in 11% of patients and out-of-field progression in 13% of patients.
Regarding the overall complication rate, focal HIFU therapy appears to be a threatening procedure in which up to 41% of patients experience some type of complication. It should be noted, however, that the majority of complications are low grade and do not require surgical intervention. The most common side-effects are temporary acute urinary retention, urethral sloughing, and UTI. One author (24) reported a slightly higher number (3%) of postoperative fistulas, but the problem was solved by increased cooling time between treatment pulses in the midzone of the prostate. Regarding self-reported symptoms and various questionnaires, initial deterioration in the urinary domain during the early postoperative phase was observed in 14% of patients with PCa. During the next few months after the procedure, significant improvement in continence rates has been observed, and 1 year after the procedure, only a low percentage of patients presented incontinence of any grade. Regarding erectile function, 70% of patients with PCa reported no changes in early the postoperative period of focal HIFU. Gradual recovery during the early postoperative phase was also observed, and 86% of patients retained sufficient erection for sexual intercourse following the procedure.

CONCLUSIONS
Focal HIFU therapy appears to be a safe procedure with low-grade complications and to offer good preservation of urinary and erectile function. Its short-term cancer control rate is encouraging, although second-line treatment or active surveillance seems to be necessary in a significant number of patients with PCa. If intermediate-and long-term oncologic outcomes are verified against standard-of-care procedures in high-quality comparative trials, focal HIFU could become the standard of care for well-selected patients with PCa. The Focal Therapy Society